The ultimate objective of this research project is the elucidation of the mechanism(s) of genetically controlled resistance to flavivirus infection, mouse hepatitis virus infection, and influenza virus infection in inbred mouse strains. In order to understand the mechanism(s) by which resistance gene products exert their limiting effects on virus replication, it is necessary to understand the particulars of the replication of the virus to which the resistance is directed. Among the three systems under study, only the replication of influenza virus has been studied to any extent. Limited information is available about the replication of flaviviruses and mouse hepatitis viruses. The studies proposed for the coming year include those aimed at study of the synthesis of viral proteins and viral RNA in susceptible cells, as well as those aimed at comparing the synthesis of viral molecules in cells from resistant and susceptible animals. Initially, the primary emphasis will be on the flavivirus system. The selection and characterization of temperature sensitive mutants will be begun as another approach to gaining a further understanding of these viruses. The existing data on the involvement of the various components of the immune system in the phenotypic expression of genetically controlled resistance in vivo is not yet sufficient for any of the three systems under investigation to draw any definite conclusions. Initially, characteristics of the cellular immune response to flavivirus will be analyzed in vitro by T cell cytotoxicity experiments and in vivo by passive transfer experiments. Subsequently, the involvement of the immune system in the expression of resistance in the mouse hepatitis and influenza resistance systems will be investigated.